酪氨酸羟化酶缺乏症导致多巴反应性肌张力不全患儿临床及遗传特点

Clinical and Genetic Characteristics of Children with Dopa-Responsive Dystonia Due to Tyrosine Hydroxylase Deficiency

【目的】探讨酪氨酸羟化酶缺乏症(THD)导致多巴反应性肌张力不全患儿的临床、遗传特点、治疗和预后。【方法】回顾分析2017年6月至2020年11月神经内科住院部收治的6例THD导致多巴反应性肌张力不全患儿的临床资料及基因检测结果。【结果】6例患儿来自4个不同家庭,男4例,女2例,均患有肌张力障碍。中位发病年龄为11.5个月(3个月~4岁),6例患者发现TH基因复合杂合突变。TH基因共检测到7个突变,包括5个已知突变c.698G>A(p.R233H)、c.1145T>C(p.I382T)、c.739G>A(p.G247S)、c.1481C>T(p.T494M)、c.880G>C(p.G294R),以及2个新突变:c.1279A>G(p.Y427H)和c.1128_1138del(p.Q377GfsTer12)。他们服用美多芭治疗,维持剂量为2~15 mg(/kg·d)。所有患者对美多芭反应良好,但病例4遗留有脊柱侧弯。【结论】THD临床表现多样,尽早识别和启动左旋多巴治疗,可明显改善预后。本研究检测到TH基因2个新的突变,错义突变c.1279A>G及移码突变c.1128_1138del。本研究拓宽了THD的基因型谱,为了解THD的分子机制提供了新思路。基因检测是THD最重要的诊断方法,对后续治疗及遗传咨询有指导意义。

【Objective】To explore the clinical and genetic characteristics,treatment and prognosis of children with do⁃pa-responsive dystonia due to tyrosine hydroxylase deficiency(THD).【Method】The clinical data of 6 children with doparesponsive dystonia due to THD,who were admitted to the Department of Neurology of Guangzhou Women and Children’s Medical Center from June 2017 to Nov 2020,were retrospectively analyzed.【Results】These 6 children(4 boys and 2 girls),who came from four different families,suffered from dystonia.The median age of onset was 11.5 months(range from 3 months to 4 years).Compound heterozygous TH gene mutations were found in six patients.Seven different mutations were identified in the TH gene including five known mutations:c.698G>A(p.R233H),c.1145T>C(p.I382T),c.739G>A(p.G247S),c.1481C>T(p.T494M),c.880G>C(p.G294)and two novel mutations:c.1279A>G(p.Y427H)and c.1128_1138de(l p.Q377GfsTer12).The patients took different doses of Madopa,ranging from 2 to 15 mg(/kg·d)in maintenance.All the patients responded well to Madopa but Case 4 was left with scoliosis【.Conclusions】THD can cause a broad range of clinical symptoms and severity.Early identification and initiation of levodopa therapy significantly improved the prognosis.We here identified two novel heterozygous variant in TH(c.1279A>G and c.1128_1138del).Our study expands the spec⁃trum of genotype of THD in China,providing new insights into the molecular mechanism of THD.Genetic testing can make a definite diagnosis.